S3-E34 – #ILC2022 Wrap-Up 1: NASH Drug Development Excitement!

S3-E34 - #ILC2022 Wrap-Up 1: NASH Drug Development Excitement!
Michelle Long and Mazen Noureddin join the Surfers (including Stephen Harrison) for a wrap-up of the major stories of #ILC2022. Much of the episode focuses on NASH Drug Development, with side conversations about the value and challenges of relying on FIB-4 or, even worse, ALT in patient screening and diagnosis.

Last week, roughly 5,000 hepatology stakeholders met at the ExCel Centre in London for The 2022 International Liver Congress (#ILC2022), the first major hepatology Congress with significant in-person attendance since the start of the COVID-19 pandemic (smaller, but very valuable, hybrid meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not). This wrap-up episode covers some of the major drug development and patient screening themes that emerged from the Congress.

Since the previous two #ILC2022 episodes did not spend much time addressing NASH drug development, moderator Roger Green suggested that this episode focused largely on drug development, with specific attention to the medications covered in the late-breaker session and Friday press conference: resmetirom, semaglutide and pemvidutide. Stephen Harrison, who presented the resmetirom late breaker and two other resmetirom studies at the conference, started by talking about the resmetirom late-breaker and other papers. The late-breaker reported initial Phase 3 results from the MAESTRO NAFLD-1 trial. The primary endpoint for this trial was safety, with several metabolic measures included as secondary endpoints. Stephen reported that on the primary endpoint, “the drug was safe and well tolerated in in over 1200 patients treated for one year with 80 or 100 milligram versus placebo.” On the secondary endpoints, there were “statistically significant reductions in anthropogenic lipids, LDL APO B triglycerides and lipo A. When we look at MRI,” he continued” “there was about a 49% overall reduction in PDF or liver fat content at week 16 and at week 50.” In the context of the secondary endpoints, Stephen went on to point out that this study took place at the height of the COVID-19 pandemic, with the result that patients in the 80mg, 100mg and placebo cohorts missed an average of two months of doses over the life of the study, which might have affected the secondary endpoints. Despite this, the drug showed significant effects in MRI-PDFF and MRE without even accounting for the way that missing dosees might have muted the drug’s impact. All told, Stephen stated there was “no bad news” in MAESTRO NAFLD-1.

He then went on to discuss the cirrhotic study. Resmetirom was safe and well-tolerated in this population and, overall, non-invasive tests moved in a way that suggested possible movement on early portal hypertensive changes. Jörn described the cirrhosis data as “thought-provoking” and related to the pathophysiology of the disease. As Stephen noted, the upcoming MAESTRO Outcomes study will afford researchers the opportunity to learn whether the pathophysiologic changes are linked to outcomes. Mazen spoke positively about the combination of changes in spleen volume, platelets and liver volume.

Michelle and Louise returned to the late-breaker to discuss results they found positive. Michelle described the study as “generalizable” in that most patients in practice miss doses, which made the results with missed doses more akin to real practice. Louise noted that providers tend to return these patients to primary care and manage them solely through diet and exercise. She reads this data to say that even in primary care, patients can improved if screened and treated properly.

At this point, Jörn discusses studies presented by him and others focusing on the accuracy of biomarkers, with specific focus on ALT and FIB-4. He discusses a presentation based on 2000 liver biopsied patients in the MAESTRO-NASH screening population. In this study of advanced patients, 26% had normal ALT levels and 80% has ALT levels less than 2x normal. Jörn makes the point that we must find ways not to miss these patients when they appear in hepatology or other practices. He notes that FIB-4 incorporates ALT and, partly as a result, we cannot trust FIB-4 to identify significant disease. After comments from Mazen and Michelle, Stephen moves on to discuss pemvidutide, a dual GLP-1/glucagon agonist.

The study is a Phase 1 with 34 patients focusing on safety and pharmacokinetics. Stephen does on to note that atherogenic lipids were reduced more than with standard weight loss. He points out highly promising results around liver fat, notes a 14-15% drop in liver volume over 6 weeks and a highly tolerable safety/side effect profile. Mazen comments that the weight loss was the most interesting finding to him. WIthin 12 weeks, 100% of patients on the 1.8mg dose achieved 5% weight loss and 55% achieved 10%. The discussion moved on to other elements of pemvidutide as well as semaglutide, which was presented for cirrhosis in another late-breaker.

Before leaving, Stephen notes that he considers the resmetirom late-breaker the most important presentation in the meeting, given how FDA evaluates medicines and how solid the safety profile looks.

After he leaves, Jörn shifts focus for the conversation to discuss the semaglutide late-breaker. The group agreed that while semaglutide showed no efficacy in reducing fibrosis for cirrhotic patients over a 48-week period, the group saw more positive signs: high level of safety coupled with the ability to meet secondary goals: weight loss, HbA1c reduction. Michelle suggested that this study might give hepatologists comfort in prescribing GLP-1 today for obese or diabetic patients with NAFLD or NASH, given all the benefits even in the absence of 48-week fibrosis reduction. Louise mentions a statin presentation she attended with a similar message about the benefit of non-NASH drugs against targets that matter to NASH patients. Roger mentions the importance of the FIB-4 and ALT studies and the group wraps up.

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